JP2023541203A - TYK2 inhibitors and their uses - Google Patents

Abstract

Described herein are compounds of formula (I) useful in treating TYK2-mediated diseases. In some embodiments, the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disorder, or a transplant-related disease. JPEG2023541203000049.jpg7999

Description

Related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63/079,217, filed September 16, 2020. The contents of which are incorporated herein by reference in their entirety.

[0002] Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and non-receptor tyrosine protein kinase 2 (also known as tyrosine kinase 2). Methods of using such compounds to inhibit ``TYK2'') are described.

Background of the invention
[0003] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are essential for cytokine signaling. TYK2 interacts with the cytoplasmic domains of type I and type II cytokine receptors and interferon type I and type III receptors, and is activated by these receptors upon cytokine binding. Cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (as limitin)). are also known), as well as interleukins (e.g. IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, L-22, IL-23, IL-27, IL- 31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokines, and LIF). Activated TYK2 in turn contains STAT1, STAT2, STAT4, and STAT6. It further phosphorylates signaling proteins such as members of the STAT family.

[0004] TYK2 activation by IL-23 is associated with inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. Genome-wide association analysis of 2,622 individuals with psoriasis confirmed an association between disease susceptibility and TYK2. Knockout of TYK2 or inhibition of tyrophotisone significantly reduces both IL-23 and IL-22-induced dermatitis.

[0005] TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucus hypersecretion are mediated by IL-13-induced activation of TYK2, which in turn activates STAT6.

[0006] Reduced TYK2 activity protects joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis. Mechanistically, reduced Tyk2 activity reduced the production of Th1/Th17-related cytokines and matrix metalloproteases, as well as other important markers of inflammation.

[0007] TYK2 knockout mice exhibited complete resistance to experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) without infiltration of CD4 T cells in the spinal cord compared to controls. . This suggests that TYK2 is essential for pathogenic CD4-mediated disease progression in MS. This supports earlier studies linking increased TYK2 expression to MS susceptibility. Loss-of-function mutations in TYK2 cause reduced demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders.

[0008] TYK2 is the only signaling messenger common to both IL-12 and IL-23. TYK2 knockout reduced methylated BSA injection-induced footpad thickness, imiquimide-induced psoriasis-like skin inflammation, and dextran sodium sulfate- or 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice.

[0009] Joint linkage of various type I IFN signaling genes in systemic lupus erythematosus (SLE, an autoimmune disease) and related studies have demonstrated that loss-of-function mutations to TYK2 and families with affected members showed a strong and significant correlation between the prevalence of SLE and the decreased prevalence of SLE. Genome-wide association analysis of individuals with SLE compared to a disease-free cohort showed a highly significant correlation between the TYK2 locus and SLE.

[0010] TYK2 has been shown to play an important role in maintaining tumor surveillance, and TYK2 knockout mice exhibited reduced cytotoxic T cell responses and accelerated tumor growth. However, these effects were associated with efficient inhibition of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors may be highly suitable for the treatment of autoimmune diseases or transplant rejection. are doing. Although other JAK family members, such as JAK3, have similar roles in the immune system, TYK2 is a better target because it involves fewer and more closely related signaling pathways and is therefore less likely to cause off-target effects. Suggested.

[0011] Studies in T-cell acute lymphoblastic leukemia (T-ALL) show that T-ALL maintains cancer cell survival by upregulating the anti-apoptotic protein BCL2 through STAT1-mediated signal transduction through TYK2. This indicates a strong dependence on IL-10. Knockdown of TYK2, but not other JAK family members, reduced cell proliferation. Specific activating mutations to TYK2 that promote cancer cell survival include those to the FERM domain (G36D, S47N, and R425H), the JH2 domain (V731I), and the kinase domain (E957D and R1027H). However, the TYK2 enzyme, characterized by an activating mutation (E957D) plus a kinase-dead mutation (M978Y or M978F), was unable to transform, thus increasing cancer cell survival. It was also confirmed that the kinase function of TYK2 is required for this purpose.

[0012] Selective inhibition of TYK2 has therefore been suggested as a suitable target for patients with IL-10 and/or BCL2-dependent tumors, such as 70% of adult T-cell leukemia cases. It has also been shown that TYK2-mediated STAT3 signaling mediates neuronal cell death caused by amyloid beta (Aβ) peptide. Reduced TYK2 phosphorylation of STAT3 after Aβ administration causes reduced neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer's patients.

[0013] Inhibition of the JAK-STAT signaling pathway is also implicated in hair growth and reversal of hair loss associated with alopecia areata.

[0014] Compounds that inhibit the activity of TYK2, particularly those with superior selectivity over JAK2, would be beneficial. Such compounds should provide a pharmacological response that advantageously treats one or more of the conditions described herein without the side effects associated with inhibition of JAK2.

[0015] There is therefore a need to provide new inhibitors that have more effective or advantageous pharmaceutically important properties, such as selectivity over other JAK kinases, particularly JAK2.

Brief overview of the invention
[0016] Described herein are compounds useful for treating TYK2-mediated diseases. In some embodiments, the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disorder, or a transplant-related disease. In some embodiments, the TYK2-mediated disease is cancer.

[0017] Disclosed herein are compounds of formula (I), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof:

During the ceremony:
L is C ₁ -C ₄ alkylene; where 1 or 2 carbon atoms may be optionally substituted by a heteroatom selected from oxygen, sulfur, nitrogen, or phosphate; L is may be substituted with one or more R ^L ;
Each R ^L is independently deuterium, halogen, -CN, -OR ^b , -NO ₂ , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C( =O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ - is C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R ^L on the same carbon together form oxo, cycloalkyl, or heterocycloalkyl;
Ring A is heteroaryl and Ring B is cycloalkyl or heterocycloalkyl;
or Ring A is aryl or heteroaryl and Ring B is heterocycloalkyl or 5-8 membered cycloalkyl;
Each R ^A is independently deuterium, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(=O)OR ^b , -OC(=O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C( =O)R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo Alkyl, aryl, and heteroaryl may be independently optionally substituted with one or more R ^A1 ;
Each R ^A1 is independently deuterium, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(=O)OR ^b , -OC(=O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C( =O)R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C _{1 -C6} aminoalkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R ^A1 on the same carbon together form oxo;
n is 0-4;
Each R ^B is independently deuterium, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(=O)OR ^b , -OC(=O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C( =O)R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo Alkyl, aryl, and heteroaryl may be independently optionally substituted with one or more R ^B1 ;
or two R ^B on the same carbon together form oxo;
Each R ^B1 is independently deuterium, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(=O)OR ^b , -OC(=O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C( =O)R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C _{1 -C6} aminoalkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R ^B1 on the same carbon together form oxo;
m is 0-4;

is a single or double bond;
X ¹ is N and X ² is -C=, or X ² is N and X ¹ is -C=;
Y ³ is CR ³ or N;
Y ⁶ is CR ⁶ or N;
Y ⁸ is CR ⁸ or N;
Y ⁹ is CR ⁹ or N;
R ³ , R ⁶ , R ⁸ , and R ⁹ are independently hydrogen, deuterium, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O) R ^a , -C(=O)OR ^b , -OC(=O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O )NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl , C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl;
R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C 1 -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C _{1 -C 6} hydroxyalkyl, C ₁ -C ₆ amino alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be optionally substituted with one or more R ^4a ;
Each R ^4a is independently deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, cycloalkyl, heterocycloalkyl, Is it aryl or heteroaryl?
or two R ^4a on the same carbon together form oxo;
R ⁵ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl;
W is -O-, -S-, or -NR ⁷ -;
R ⁷ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl;
Each R ^a is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally one or more of oxo, deuterium, halogen, -CN, -OH, -OMe, -NH ₂ , -C(=O)Me, -C(=O)OH, -C(=O)OMe , C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;
Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally one or more of oxo, deuterium, halogen, -CN, -OH, -OMe, -NH ₂ , -C(=O)Me, -C(=O)OH, -C(=O ) OMe, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;
Each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ amino alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently optionally includes one or more of oxo, deuterium, halogen, -CN, -OH, -OMe, -NH ₂ , -C(=O)Me, -C(=O)OH, - optionally substituted with C(=O)OMe, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;
or R ^c and R ^d together with the nitrogen atom to which they are attached optionally contain one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH ₂ , -C( =O)Me, -C(=O)OH, -C(=O)OMe, _C1 - _C6 alkyl, or _C1 - _C6 haloalkyl to form a heterocycloalkyl optionally substituted.

[0018] Also provided herein is a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof; Pharmaceutical compositions containing excipients are also disclosed.

[0019] Also described herein is a method of inhibiting the TYK2 enzyme in a patient or biological sample, the method comprising treating said patient or biological sample with a compound disclosed herein, or a pharmaceutically acceptable compound thereof. Also disclosed are methods comprising contacting a salt, stereoisomer, or solvate with a salt, stereoisomer, or solvate.

[0020] It also includes administering a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, to a patient in need thereof. Also disclosed herein are methods of treating diseases caused by cancer. In some embodiments, the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disorder, or a transplant-related disease. In some embodiments, the disease is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.

Inclusion by reference
[0021] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purpose identified herein.

Detailed description and definition of the invention
[0022] As used in this specification and the appended claims, the singular forms "a,""an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes one or more cells (or cell) and equivalents thereof known to those skilled in the art, and the like. When ranges are used herein for a physical property, such as molecular weight, or a chemical property, such as a chemical formula, all combinations and subcombinations of the ranges and specific embodiments therein are included. It is intended that The term "about" for a number or range of numbers means that the number or range of numbers referred to is an approximation within experimental variation (or within statistical experimental error), so that the number or range of numbers is in some cases means varying from 1% to 15% of the stated number or numerical range. The term "comprising" (and related terms, such as "comprise" or "comprises" or "having" or "including"), in certain other embodiments, includes, for example, any of the herein described The term "consist of" or "consist essentially of" the feature for which an embodiment of a composition, composition, method, or process is described. )” is not intended to be excluded.

[0023] As used in this specification and the appended claims, the following terms have the meanings set forth below unless specified to the contrary.

[0024] "Oxo" means =O.

[0025] "Alkyl" means an optionally substituted straight chain, or an optionally substituted branched, saturated chain having from 1 to about 10 carbon atoms, or from 1 to 6 carbon atoms. means a monovalent group of a hydrocarbon. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl- 1-Butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl- 2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n- Includes butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, as well as longer alkyl groups such as heptyl, octyl, and the like. Whenever it appears herein, numerical ranges such as "C ₁ -C ₆ alkyl" refer to ranges in which the alkyl group has 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms. , 5 carbon atoms or 6 carbon atoms, but this definition also includes the presence of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C ₁ -C ₁₀ alkyl, C ₁ -C ₉ alkyl, C ₁ -C ₈ alkyl, C ₁ -C ₇ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₅ alkyl , C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl, or C ₁ alkyl. Unless specifically stated otherwise herein, alkyl groups may optionally include, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. may be replaced with In some embodiments, alkyl may be optionally substituted with oxo, halogen, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -CF ₃ , -OH, or -OMe. In some embodiments, alkyl is optionally substituted with halogen.

[0026] "Alkenyl" has one or more carbon-carbon double bonds and is optionally substituted having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. refers to a straight-chain or optionally substituted branched hydrocarbon monovalent group. It is to be understood that the groups may be in the cis or trans configuration with respect to the double bond and include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH ₂ ), 1-propenyl (-CH ₂ CH=CH ₂ ), isopropenyl [-C(CH ₃ )=CH ₂ ], butenyl, Examples include 1,3-butadienyl. Whenever it appears herein, numerical ranges such as "C ₂ -C ₆ alkenyl" refer to ranges in which the alkenyl group has 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms. or 6 carbon atoms, but this definition also includes the presence of the term "alkenyl" where no numerical range is specified. In some embodiments, alkenyl is C ₂ -C ₁₀ alkenyl, C ₂ -C ₉ alkenyl, C 2 -C ₈ alkenyl, C _{2 -C 7} alkenyl, C ₂ -C ₆ alkenyl, C ₂ -C ₅ alkenyl , C ₂ -C ₄ alkenyl, C ₂ -C ₃ alkenyl, or C ₂ alkenyl. Unless stated otherwise specifically herein, alkenyl groups optionally include, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, It may be replaced with, etc. In some embodiments, alkenyl may be optionally substituted with oxo, halogen, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, alkenyl may be optionally substituted with oxo, halogen, -CN, _-CF3 , -OH, or -OMe. In some embodiments, alkenyl is optionally substituted with halogen.

[0027] "Alkynyl" has one or more carbon-carbon triple bonds and is optionally substituted having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. means a straight-chain or optionally substituted branched hydrocarbon monovalent group. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, numerical ranges such as "C ₂ -C ₆ alkynyl" refer to the ranges in which the alkynyl group contains 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms. or 6 carbon atoms, but this definition also includes the presence of the term "alkynyl" where no numerical range is specified. In some embodiments, alkynyl is C ₂ -C ₁₀ alkynyl, C 2 -C ₉ alkynyl, C ₂ -C ₈ alkynyl, C _{2 -C 7} alkynyl, C ₂ -C ₆ alkynyl, C ₂ -C ₅ alkynyl , C ₂ -C ₄ alkynyl, C ₂ -C ₃ alkynyl, or C ₂ alkynyl. Unless specifically stated otherwise herein, alkynyl groups may optionally include, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. may be replaced with In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -CF ₃ , -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0028] "Alkylene" means a straight or branched divalent hydrocarbon chain. Unless specifically stated otherwise herein, alkylene groups are optionally, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. may be replaced with . In some embodiments, alkylene may be optionally substituted with oxo, halogen, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, alkylene may be optionally substituted with oxo, halogen, -CN, _-CF3 , -OH, or -OMe. In some embodiments, alkylene may be optionally substituted with halogen.

[0029] "Alkoxy" means a group of the formula -Oalkyl, where alkyl is as defined above. Unless specifically stated otherwise herein, alkoxy groups optionally include, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. may be replaced with . In some embodiments, alkoxy may be optionally substituted with oxo, halogen, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, alkoxy may be optionally substituted with oxo, halogen, -CN, _-CF3 , -OH, or -OMe. In some embodiments, alkoxy may be optionally substituted with halogen.

[0030] "Aminoalkyl" means an alkyl group as defined above substituted with one or more amines. In some embodiments, alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with 1, 2, or 3 amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, aminoalkyl is aminomethyl.

[0031] "Aryl" means a group derived from a hydrocarbon ring system containing hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. Aryl groups can be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which are fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded) or bridged ring systems. In some embodiments, the aryl is a 6-10 membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl groups include, but are not limited to, anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene. , phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. In some embodiments, aryl is phenyl. Unless specifically stated otherwise herein, aryl may optionally include, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, hetero May be substituted with aryl, etc. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, _-CF3 , -OH, or -OMe. In some embodiments, aryl is optionally substituted with halogen.

[0032] "Cycloalkyl" means a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which when fused (fused with an aryl or heteroaryl ring), cycloalkyl (attached via aromatic ring atoms) or bridged ring systems. Representative cycloalkyls include, but are not limited to, 3-15 carbon atoms, 3-10 carbon atoms, 3-8 carbon atoms, 3-6 carbon atoms, 3-15 carbon atoms, cycloalkyl having 5 carbon atoms, or 3 to 4 carbon atoms (respectively, C ₃ -C ₁₅ cycloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₅ cycloalkyl, or C ₃ -C ₄ cycloalkyl). In some embodiments, the cycloalkyl is a 3-6 membered cycloalkyl. In some embodiments, the cycloalkyl is a 5-6 membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl or carbocycle include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[ 2.1.1] hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and There is 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless specifically stated otherwise herein, cycloalkyl may optionally include, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclo May be substituted with alkyl, heteroaryl, etc. In some embodiments, cycloalkyl may be optionally substituted with oxo, halogen, methyl, ethyl, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, _-CF3 , -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0033] "Deuteroalkyl" means an alkyl group as defined above substituted with one or more deuterium atoms. In some embodiments, the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with 1, 2, or 3 deuterium atoms. In some embodiments, the alkyl is substituted with 1, 2, 3, 4, 5, or 6 deuterium atoms. _Deuteroalkyl includes, for example, _{CD3 , CH2D} , CHD2, _CH2CD3 , _{CD2CD3 , CHDCD3} , _{CH2CH2D ,} or _{CH2CHD2 .} In some embodiments, deuteroalkyl is _CD3 .

[0034] "Haloalkyl" means an alkyl group as defined above substituted with one or more halogen atoms. In some embodiments, the alkyl is substituted with 1, 2, or 3 halogen atoms. In some embodiments, the alkyl is substituted with 1, 2, 3, 4, 5, or 6 halogens. Examples of haloalkyl include trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromo Ethyl, etc. In some embodiments, haloalkyl is trifluoromethyl.

[0035] "Halo" or "halogen" means bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0036] "Heteroalkyl" means that one or more backbone atoms of the alkyl are derived from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. means a selected alkyl group. The heteroalkyl is attached to the remainder of the molecule at the heteroalkyl carbon atom. In one aspect, a heteroalkyl is a C ₁ -C ₆ heteroalkyl, and a heteroalkyl has 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, - N(alkyl)-), sulfur, or combinations thereof, the heteroalkyl is attached to the remainder of the molecule at the heteroalkyl carbon atom. Examples of such heteroalkyls are, for example, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₂ CH ₂ OCH ₃ or -CH(CH ₃ )OCH ₃ . Unless specifically stated otherwise herein, heteroalkyl may optionally include, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclo May be substituted with alkyl, heteroaryl, etc. In some embodiments, the heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, _-CF3 , -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted with halogen.

[0037] "Hydroxyalkyl" means an alkyl group as defined above substituted with one or more hydroxyl. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with 1, 2, or 3 hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, hydroxyalkyl is hydroxymethyl.

[0038] "Heterocycloalkyl" means a 3- to 24-membered partially or fully atom containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. means a saturated ring group. In some embodiments, a heterocycloalkyl contains 1 or 2 heteroatoms selected from nitrogen and oxygen. Unless stated otherwise specifically herein, a heterocycloalkyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which is a fused (aryl or heteroaryl ring). When fused with, the heterocycloalkyl may include a non-aromatic ring atom attached) or a bridged ring system; the nitrogen, carbon or sulfur atoms in the heterocycloalkyl group may be optionally oxidized; The nitrogen atom may optionally be quaternized. Representative heterocycloalkyls include, but are not limited to, 2-15 carbon atoms, 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, 2 ~5 carbon atoms, or heterocycloalkyl having 2 to 4 carbon atoms (respectively, C ₂ -C ₁₅ heterocycloalkyl, C ₂ -C ₁₀ heterocycloalkyl, C ₂ -C ₈ heterocycloalkyl, C ₂ -C ₆ heterocycloalkyl, C ₂ -C ₅ heterocycloalkyl, or C ₂ -C ₄ heterocycloalkyl). In some embodiments, a heterocycloalkyl is a 3-6 membered heterocycloalkyl. In some embodiments, the cycloalkyl is a 5-6 membered heterocycloalkyl. Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isothiazolidinyl, Xazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl , pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo- 1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. When referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is equal to the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the backbone atoms of the heterocycloalkyl ring). It is understood that this is not the case. Unless specifically stated otherwise herein, heterocycloalkyl may optionally include, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, May be substituted with heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, _-CF3 , -OH, or -OMe. In some embodiments, a heterocycloalkyl is optionally substituted with halogen.

[0039] "Heteroaryl" includes a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. ~14-membered ring system group. Heteroaryl groups can be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which are fused (when fused with a cycloalkyl or heterocycloalkyl ring, heteroaryl contains aromatic ring atoms). nitrogen, carbon or sulfur atoms in a heteroaryl group may also be optionally oxidized; nitrogen atoms may optionally be quaternized. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1 , 4] dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxynyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranyl, benzothienyl (benzothiophenyl) ), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl , indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, Thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (ie, thienyl). Unless specifically stated otherwise herein, heteroaryl may optionally include, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl , heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, _-CF3 , -OH, or -OMe. In some embodiments, a heteroaryl is optionally substituted with halogen.

[0040] The terms "treat," "prevent," "ameliorate," and "inhibit," and words derived therefrom, as used herein, do not necessarily mean 100% or complete treatment, Does not mean prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition that those skilled in the art would recognize as having some potential benefit or therapeutic effect. In this regard, the disclosed methods can provide any level of treatment, prevention, amelioration, or inhibition of any amount of disease in a mammal. For example, a disease, including its symptoms or conditions, may be about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20% , or about 10%. It should be noted that the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein refers to the treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disease, e.g., cancer or inflammatory disease. can include inhibition. Also, for purposes of the present invention, "treatment," "prevention," "improvement," or "inhibition" includes delaying the onset of a disease, or a symptom or condition thereof.

[0041] The term "effective amount" or "therapeutically effective amount," as used herein, refers to one or more symptoms of the disease or condition being treated, such as cancer or an inflammatory disease. It means a sufficient amount of a compound disclosed herein to be administered to provide some relief. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. In some embodiments, the appropriate "effective" amount for a particular case is determined using techniques such as dose escalation studies.

[0042] As used herein, the term "TYK2-mediated" disorder, disease, and/or condition refers to a disorder, disease, and/or condition in which TYK2 or a mutant thereof plays a role. means any known disease or other harmful condition. Accordingly, another embodiment relates to treating or reducing the severity of one or more diseases in which TYK2 or mutants thereof are known to play a role. Such TYK2-mediated diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological disorders, and transplant-related diseases.

Compound
[0043] Described herein are compounds useful for treating TYK2-mediated diseases. In some embodiments, the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disorder, or a transplant-related disease. In some embodiments, the TYK2-mediated disease is cancer.

[0044] Disclosed herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

During the ceremony:
L is C ₁ -C ₄ alkylene; where 1 or 2 carbon atoms may be optionally substituted by heteroatoms selected from oxygen, sulfur, nitrogen, or phosphate; L is optionally 1 May be substituted with the above R ^L ;
Each R ^L is independently deuterium, halogen, -CN, -OR ^b , -NO ₂ , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C( =O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ - is C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R ^L on the same carbon together form oxo, cycloalkyl, or heterocycloalkyl;
Ring A is heteroaryl and Ring B is cycloalkyl or heterocycloalkyl;
or Ring A is aryl or heteroaryl and Ring B is heterocycloalkyl or 5-8 membered cycloalkyl;
Each R ^A is independently deuterium, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(=O)OR ^b , -OC(=O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C( =O)R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo Alkyl, aryl, and heteroaryl may be independently optionally substituted with one or more R ^A1 ;
Each R ^A1 is independently deuterium, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(=O)OR ^b , -OC(=O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C( =O)R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C _{1 -C6} aminoalkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R ^A1 on the same carbon together form oxo;
n is 0-4;
Each R ^B is independently deuterium, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(=O)OR ^b , -OC(=O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C( =O)R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo Alkyl, aryl, and heteroaryl may be independently optionally substituted with one or more R ^B1 ;
or two R ^B on the same carbon together form oxo;
Each R ^B1 is independently deuterium, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(=O)OR ^b , -OC(=O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C( =O)R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C _{1 -C6} aminoalkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R ^B1 on the same carbon together form oxo;
m is 0-4;

is a single or double bond;
X ¹ is N and X ² is -C=, or X ² is N and X ¹ is -C=;
Y ³ is CR ³ or N;
Y ⁶ is CR ⁶ or N;
Y ⁸ is CR ⁸ or N;
Y ⁹ is CR ⁹ or N;
R ³ , R ⁶ , R ⁸ , and R ⁹ are independently hydrogen, deuterium, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O) R ^a , -C(=O)OR ^b , -OC(=O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O )NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl , C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl;
R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C 1 -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C _{1 -C 6} hydroxyalkyl, C ₁ -C ₆ amino alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be optionally substituted with one or more R ^4a ;
Each R ^4a is independently deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, cycloalkyl, heterocycloalkyl, Is it aryl or heteroaryl?
or two R ^4a on the same carbon together form oxo;
R ⁵ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl;
W is -O-, -S-, or -NR ⁷ -;
R ⁷ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl;
Each R ^a is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally one or more of oxo, deuterium, halogen, -CN, -OH, -OMe, -NH ₂ , -C(=O)Me, -C(=O)OH, -C(=O)OMe , C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;
Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally one or more of oxo, deuterium, halogen, -CN, -OH, -OMe, -NH ₂ , -C(=O)Me, -C(=O)OH, -C(=O ) OMe, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;
Each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ amino alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl; and heteroaryl independently optionally includes one or more of oxo, deuterium, halogen, -CN, -OH, -OMe, -NH ₂ , -C(=O)Me, -C(=O)OH, - optionally substituted with C(=O)OMe, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;
or R ^c and R ^d together with the nitrogen atom to which they are attached optionally contain one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH ₂ , -C( =O)Me, -C(=O)OH, -C(=O)OMe, forming a heterocycloalkyl optionally substituted with _C1 - _C6 alkyl, or _C1 - _C6 haloalkyl.

[0045] In some embodiments, the compound of formula (I) is of formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0046] In some embodiments, the compound of formula (I) is of formula (Ib), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0047] In some embodiments, the compound of formula (I) is of formula (Ic), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0048] In some embodiments, the compound of formula (I) is of formula (Id), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0049] In some embodiments, the compound of formula (I) is of formula (Ie), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0050] In some embodiments, the compound of formula (I) is of formula (If), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0051] In some embodiments, the compound of formula (I) is of formula (Ig), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0052] In some embodiments, the compound of formula (I) is of formula (Ih), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0053] In some embodiments, the compound of formula (I) is of formula (Ii), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0054] In some embodiments, the compound of formula (I) is of formula (Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0055] In some embodiments, the compound of formula (I) is of formula (Ik) or formula (Il), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

where at least each R is independently H or D, and at least one R is D.

[0056] In some embodiments, the compound of formula (I) is of formula (Im) or formula (In), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

where at least each R is independently H or D, and at least one R is D.

[0057] In some embodiments, the compound of formula (I) is of formula (Io) or formula (Ip), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

where at least each R is independently H or D, and at least one R is D.

[0058] In some embodiments, the compound of formula (I) is of formula (Iq) or formula (Ir), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

where at least each R is independently H or D, and at least one R is D.

[0059] In some embodiments, the compound of formula (I) is of formula (Is) or formula (It), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

where at least each R is independently H or D, and at least one R is D.

[0060] In some embodiments of the compounds of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Ring A is heteroaryl. and Ring B is cycloalkyl or heterocycloalkyl.

[0061] In some embodiments of the compounds of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Ring A is aryl or hetero aryl and Ring B is heterocycloalkyl.

[0062] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Ring A is aryl or hetero is aryl, and ring B is a 5- to 8-membered cycloalkyl.

[0063] In some embodiments of the compounds of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring B is 5-6 It is a member cycloalkyl.

[0064] In some embodiments of the compounds of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring B is a 5-membered It is cycloalkyl.

[0065] In some embodiments of the compounds of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring B is 5-6 member heterocycloalkyl.

[0066] In some embodiments of the compounds of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring B is a 5-membered It is heterocycloalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ij), or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, ring B is tetrahydrofuran or pyrrolidine. In some embodiments of compounds of formula (I) or (Ia)-(Ij), or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, ring B is tetrahydrofuran.

[0067] In some embodiments of the compounds of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Ring A is bicyclic is a heteroaryl. In some embodiments of the compounds of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Ring A is indolyl, indazolyl, benzimidazolyl. , benzotriazolyl, benzothiophenyl, benzothiazolyl, benzofuranyl, or benzoxazolyl.

[0068] In some embodiments of the compounds of Formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Ring A is monocyclic is a heteroaryl. In some embodiments of the compounds of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ring A is pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl.

[0069] In some embodiments of the compounds of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Ring A is phenyl. .

[0070] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y ⁹ is N. . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y ⁹ is CR ⁹ . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁹ is hydrogen, deuterium, halogen , -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, or C ₁ -C ₆ aminoalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁹ is hydrogen, deuterium, halogen , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁹ is hydrogen, deuterium, halogen , or C ₁ -C ₆ alkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁹ is hydrogen, halogen, or C ₁ - _C6 alkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁹ is hydrogen.

[0071] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y ⁶ is N. . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y ⁶ is CR ⁶ . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁶ is hydrogen, deuterium, halogen , -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, or C ₁ -C ₆ aminoalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁶ is hydrogen, deuterium, halogen , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁶ is hydrogen, deuterium, halogen , or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ij), or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, R ⁶ is hydrogen, halogen, or C ₁ - _C6 alkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁶ is hydrogen.

[0072] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, ^Y3 is N. . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y ³ is CR ³ . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ³ is hydrogen, deuterium, halogen , -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, or C ₁ -C ₆ aminoalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ³ is hydrogen, deuterium, halogen , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ³ is hydrogen, deuterium, halogen , or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ij), or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, R ³ is hydrogen, halogen, or C ₁ - _C6 alkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ³ is hydrogen.

[0073] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y ⁸ is N. . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Y ⁸ is CR ⁸ . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁸ is hydrogen, deuterium, halogen , -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, or C ₁ -C ₆ aminoalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁸ is hydrogen, deuterium, halogen , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁸ is hydrogen, deuterium, halogen , or C ₁ -C ₆ alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ij), or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, R ⁸ is hydrogen, halogen, or C ₁ - _C6 alkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁸ is hydrogen.

[0074] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁴ is C ₁ -C ₆ alkyl or C ₁ -C ₆ deuteroalkyl.

[0075] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁵ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl.

[0076] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁵ is C ₁ - C ₆ alkyl or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁵ is hydrogen.

[0077] In some embodiments of the compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, W is -S- be. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, W is -O-.

[0078] In some embodiments of the compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, W is ^-NR7- It is. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁷ is hydrogen or C ₁ -C ₆ alkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁷ is hydrogen. In some embodiments of the compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R ⁷ is C ₁ -C ₆ alkyl It is.

[0079] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^A is independently deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R ^A1 . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^A is independently deuterium , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C 1 -C ₆ deuteroalkyl, C _{1 -C 6} hydroxyalkyl, C ₁ -C ₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl , or heteroaryl; where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R ^A1 . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^A is independently deuterium , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, aryl, or heteroaryl; where each alkyl, aryl, and heteroaryl independently represents may be substituted with one or more R ^A1 . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^A is independently deuterium , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^A is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^A is independently C ₁ -C ₆ deuteroalkyl.

[0080] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^A1 is independently deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; be. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^A1 is independently deuterium , halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^A1 is independently deuterium , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^A1 is independently deuterium , halogen, or C ₁ -C ₆ alkyl.

[0081] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 0-2. be. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 0 or 1. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 1 or 2. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 0. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 1. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 2. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, n is 3.

[0082] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^B is independently deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R ^B1 . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^B is independently deuterium , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C 1 -C ₆ deuteroalkyl, C _{1 -C 6} hydroxyalkyl, C ₁ -C ₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl , or heteroaryl; where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R ^B1 . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^B is independently deuterium , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, aryl, or heteroaryl; where each alkyl, aryl, and heteroaryl independently represents may be substituted with one or more R ^B1 . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^B is independently deuterium , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^B is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^B is independently C ₁ -C ₆ alkyl.

[0083] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^B1 is independently deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; be. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^B1 is independently deuterium , halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^B1 is independently deuterium , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^B1 is independently deuterium , halogen, or C ₁ -C ₆ alkyl.

[0084] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 0-2. be. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 0 or 1. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 1 or 2. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 0. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 1. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 2. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, m is 3.

[0085] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is _C2 -C ₄ alkylene; where one carbon atom may be optionally substituted by a heteroatom selected from oxygen, sulfur, or nitrogen; L may be optionally substituted with one or more R ^L . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C ₂ -C ₄ alkylene. where one carbon atom may be optionally substituted by a heteroatom selected from oxygen or sulfur; L may be optionally substituted with one or more R ^L. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C ₂ -C ₄ alkylene. where one carbon atom may be optionally substituted with oxygen; L may be optionally substituted with one or more R ^L. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C ₂ -C ₄ alkylene. where one carbon atom is replaced by a heteroatom selected from oxygen, sulfur, or nitrogen; L may optionally be substituted with one or more R ^L. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C ₂ -C ₄ alkylene. where one carbon atom is substituted by a heteroatom selected from oxygen or sulfur; L may optionally be substituted with one or more R ^L.

[0086] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is _C2 -C ₄ alkylene; where one carbon atom is replaced by oxygen; L may be optionally substituted with one or more R ^L.

[0087] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is _C2 -C ₃ alkylene; where one carbon atom may be optionally substituted by a heteroatom selected from oxygen, sulfur, or nitrogen; L may be optionally substituted with one or more R ^L . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C ₂ -C ₃ alkylene. where one carbon atom may be optionally substituted by a heteroatom selected from oxygen or sulfur; L may be optionally substituted with one or more R ^L. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C ₂ -C ₃ alkylene. where one carbon atom may be optionally substituted by an oxygen atom; L may be optionally substituted with one or more R ^L. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C ₂ -C ₃ alkylene. where one carbon atom is replaced by a heteroatom selected from oxygen, sulfur, or nitrogen; L may optionally be substituted with one or more R ^L. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C ₂ -C ₃ alkylene. where one carbon atom is substituted by a heteroatom selected from oxygen or sulfur; L may optionally be substituted with one or more R ^L. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C ₂ -C ₃ alkylene. where one carbon atom may be optionally substituted by an oxygen atom; L may be optionally substituted with one or more R ^L.

[0088] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C _-alkylene where one carbon atom may be optionally substituted by a heteroatom selected from oxygen, sulfur, or nitrogen; L may be optionally substituted with one or more R ^L . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C _-alkylene ; One carbon atom here may be optionally substituted by a heteroatom selected from oxygen or sulfur; L may optionally be substituted with one or more R ^L . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C _-alkylene ; One carbon atom here may be optionally substituted by an oxygen atom; L may optionally be substituted with one or more R ^L. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C _-alkylene ; where one carbon atom is substituted by a heteroatom selected from oxygen, sulfur, or nitrogen; L may optionally be substituted with one or more R ^L . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C _-alkylene ; One carbon atom here is substituted by a heteroatom selected from oxygen or sulfur; L may optionally be substituted with one or more R ^L . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C _-alkylene ; One carbon atom here is replaced by an oxygen atom; L may optionally be substituted with one or more R ^L.

[0089] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C ₂ -alkylene where one carbon atom may be optionally substituted by a heteroatom selected from oxygen, sulfur, or nitrogen; L may be optionally substituted with one or more R ^L . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C ₂ -alkylene; One carbon atom here may be optionally substituted by a heteroatom selected from oxygen or sulfur; L may optionally be substituted with one or more R ^L . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C ₂ -alkylene; One carbon atom here may be optionally substituted by an oxygen atom; L may optionally be substituted with one or more R ^L. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C ₂ -alkylene; where one carbon atom is substituted by a heteroatom selected from oxygen, sulfur, or nitrogen; L may optionally be substituted with one or more R ^L . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C ₂ -alkylene; One carbon atom here is substituted by a heteroatom selected from oxygen or sulfur; L may optionally be substituted with one or more R ^L . In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is C ₂ -alkylene; One carbon atom here is replaced by an oxygen atom; L may optionally be substituted with one or more R ^L.

[0090] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^L is independently deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl , C ₁ -C ₆ hydroxyalkyl, or C ₁ -C ₆ aminoalkyl; or two R ^L on the same carbon together form oxo, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^L is independently deuterium , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl; or two R ^L on the same carbon taken together to form oxo, cycloalkyl, or Forms a heterocycloalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^L is independently deuterium , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl.

[0091] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is _-CH2- O-, -O-CH ₂ -, -CH ₂ -S-, or -S-CH ₂ -. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, L is _-CH2 -O- or -O-CH ₂ -.

[0092] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^a is independently is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, or cycloalkyl; where each alkyl and cycloalkyl is independently optionally one or more of oxo, Deuterium, halogen, -CN, -OH, -OMe, -NH ₂ , -C(=O)Me, -C(=O)OH, -C(=O)OMe, C ₁ -C ₆ alkyl, or Optionally substituted with C ₁ -C ₆ haloalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^a is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of the compounds described above, each R ^a is independently C ₁ -C ₆ alkyl.

[0093] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^b is independently is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, or cycloalkyl; where each alkyl and cycloalkyl independently optionally represents one or more Oxo, deuterium, halogen, -CN, -OH, -OMe, -NH ₂ , -C(=O)Me, -C(=O)OH, -C(=O)OMe, C ₁ -C ₆ alkyl , or C ₁ -C ₆ haloalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of the compounds described above, each R ^b is independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds described above, each R ^b is hydrogen. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^b is independently C ₁ -C ₆ alkyl.

[0094] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each of R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, or cycloalkyl; where each alkyl and cycloalkyl is independently optional one or more of oxo, deuterium, halogen, -CN, -OH, -OMe, -NH ₂ , -C(=O)Me, -C(=O)OH, -C(=O)OMe, C ₁ May be substituted with -C ₆ alkyl or C ₁ -C ₆ haloalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^c and R ^d are independently and hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^c and R ^d are independently and hydrogen or C ₁ -C ₆ alkyl. In some embodiments of the compounds described above, each R ^c and R ^d is hydrogen. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each R ^c and R ^d are independently and C ₁ -C ₆ alkyl.

[0095] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each L, R ^A , R ^B , R ⁴ , R ^a , R ^b , R ^c , and R ^d are independently substituted with 1, 2, 3, or 4 substituents as defined herein. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each L, R ^A , R ^B , R ⁴ , R ^a , R ^b , R ^c , and R ^d may be independently optionally substituted with 1, 2, or 3 substituents as defined herein. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each L, R ^A , R ^B , R ⁴ , R ^a , R ^b , R ^c , and R ^d may be independently optionally substituted with one or two substituents as defined herein. In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, each L, R ^A , R ^B , R ⁴ , R ^a , R ^b , R ^c , and R ^d may be independently optionally substituted with one substituent as defined herein.

[0096] In some embodiments of a compound of formula (I) or (Ia)-(Ij), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, the compound is

, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

Further Forms of the Compounds Disclosed herein Isomers/Stereoisomers
[0097] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some situations, the compounds described herein have one or more chiral centers, and each center exists in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms and corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures, combinations, or interconversions of enantiomers and/or diastereomers resulting from a single preparative step are suitable for the uses described herein. Useful. In some embodiments, the compounds described herein are prepared by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomeric compounds and separating the diastereomers. , prepared as individual stereoisomers by recovering the optically pure enantiomer. In some embodiments, complexes that can be separated are preferred. In some embodiments, diastereomers have different physical properties (eg, melting points, boiling points, solubility, reactivity, etc.) and are separated by taking advantage of these differences. In some embodiments, diastereomers are separated by chiral chromatography or preferably by separation/resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomer is then recovered along with the resolving agent.

labeled compound
[0098] In some embodiments, a compound described herein exists in its isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are the same as those described herein, but with one or more atoms normally Substituted by an atom having an atomic mass or mass number different from that found in nature. Examples of isotopes that can be incorporated into the compounds described herein, or solvates or stereoisomers thereof, include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride. The isotopes include, for example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl, respectively. Compounds described herein containing the foregoing isotopes and/or other isotopes of other atoms, and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are within the scope of this disclosure. It is within. Certain isotopically labeled compounds, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, ie, ³ H, and carbon-14, ie, ¹⁴ C isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavy isotopes such as deuterium or ² H yields several therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.

[0099] In some embodiments, the compounds described herein are labeled by other means, such as, but not limited to, the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

pharmaceutically acceptable salts
[00100] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[00101] In some embodiments, the compounds described herein have acidic or basic groups and, therefore, can contain several inorganic or organic bases and any of inorganic and organic acids. Reacts with to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting the purified compound in its free form with a suitable acid or base. and isolating the salt thus formed.

[00102] Examples of pharmaceutically acceptable salts include salts prepared by reaction of a compound described herein with a mineral, organic acid, or inorganic base, such as acetates, acrylates, adipine. Acid salts, alginates, aspartates, benzoates, benzenesulfonates, bisulfates, bisulfites, bromides, butyrates. Butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, diglucone acid salt, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, Hexanoate, hexyne-1,6-diode, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide , isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, hydrogen phosphate, 1- Naphthalene sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, palmoate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pyruvic acid Salt, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinic acid There are salts such as suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconate, and xylene sulfonate.

[00103] Additionally, the compounds described herein can be used in free base form with pharmaceutically acceptable inorganic or organic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. and inorganic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, etc. p-Toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2 -ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4, 4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethyl acetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid , and pharmaceutically acceptable salts formed by reaction with organic acids such as muconic acid.

[00104] In some embodiments, a compound described herein that includes a free acid group is a hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation. with a suitable base, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Typical salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts, and the like. Examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N ⁺ (C _1-4 alkyl) ₄ , and the like.

[00105] Representative organic amines useful in the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is to be understood that the compounds described herein also include quaternized versions of the basic nitrogen-containing groups they contain. In some embodiments, water or oil soluble or dispersible products are obtained by such quaternization.

solvate
[00106] In some embodiments, the compounds described herein exist as solvates. The present disclosure provides methods of treating diseases by administering such solvates. The present disclosure further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[00107] Solvates contain stoichiometric or non-stoichiometric amounts of solvent, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. Additionally, the compounds provided by the present invention can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided by this invention.

tautomer
[00108] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers that fall within the formulas described herein. Tautomers are compounds that are interconvertible by movement of a hydrogen atom accompanied by exchange of a single bond and an adjacent double bond. A chemical equilibrium of tautomers exists in bond configurations that can be tautomerized. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors including temperature, solvent, and pH.

Preparation of compounds
[00109] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in the art starting from commercially available chemicals and/or from compounds described in the chemical literature. . "Commercially available chemicals" are commercially available from standard commercial sources, e.g., Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI; e.g., Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chem Services Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[00110] Appropriate reference books and articles detailing the synthesis or referring to articles describing the preparation of reactants useful in the preparation of the compounds described herein include, e.g., "Synthetic Organic Chemistry" ”, John Wiley & Sons, Inc. , New York; R. Sandler et al. , “Organic Functional Group Preparations”, 2nd Ed. , Academic Press, New York, 1983; O. House, “Modern Synthetic Reactions”, 2nd Ed. , W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed. , John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed. , Wiley-Interscience, New York, 1992. Additional suitable reference books and articles that refer to articles detailing the synthesis or describing the preparation of reactants useful in the preparation of the compounds described herein include, for example, Fuhrhop, J.; and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISB N:3-527-29074-5; Hoffman, R. V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-190 31-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; O Tera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C. , "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: St. "Arting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN :3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional "Groups" by John Wiley & Sons, in 73 volumes.

[00111] Specific and similar reactants are optionally identified through the index of known chemicals prepared by the American Chemical Society's Chemical Abstracts Service, available at most public and university libraries, and online. Chemicals that are known but not commercially available in catalogs may sometimes be prepared by custom chemical synthesis companies, and many standard chemical supply companies (e.g., see list above) provide custom synthesis services. provide services; References for the preparation and selection of pharmaceutical salts of the compounds described herein include P. H. Stahl & C. G. Wermuth, "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

pharmaceutical composition
[00112] In certain embodiments, the compounds described herein are administered as pure chemicals. In some embodiments, the compounds described herein are those described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 ^st Ed. Mack Pub. Co., Easton, PA (2005)). A pharmaceutically suitable or acceptable carrier (herein referred to as a pharmaceutically suitable (or acceptable) excipient, physiological (also referred to as a physiologically suitable (or acceptable) carrier).

[00113] Accordingly, a pharmaceutical composition comprising a compound described herein according to the invention, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient. things are provided.

[00114] In certain embodiments, the compounds provided by the invention contain about 50% of other small organic molecules, such as, for example, unreacted intermediates or synthetic byproducts created in one or more steps of a synthetic method. %, or less than about 1%, or less than about 0.1%.

[00115] The pharmaceutical composition is administered in a manner appropriate to the disease being treated (or prevented). The appropriate dose and duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, appropriate doses and treatment regimens will provide improved therapeutic and/or preventive benefits, such as faster complete or partial remission, or longer disease-free and/or overall survival, or reduced severity of symptoms. the composition in an amount sufficient to provide clinical results). Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends on the patient's body mass, weight, or blood volume.

[00116] In some embodiments, the pharmaceutical compositions are oral, topical (including buccal and sublingual), rectal, intravaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal, and intrathecal. Formulated for external as well as intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous, oral, inhalation, intranasal, topical, or intraocular administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is a tablet, pill, capsule, liquid, inhalant, nasal spray, suppository, suspension, gel, colloid, dispersion, suspension, solution, emulsion, ointment, Formulated as lotions, eye drops, or ear drops. In some embodiments, the pharmaceutical composition is formulated as a tablet.

[00117] Appropriate doses and dosing regimens are determined by traditional range-finding techniques known to those of skill in the art. Generally, treatment is initiated with smaller doses that are less than the optimal dose of the compounds disclosed herein. Thereafter, the dose is increased in small increments until the optimal effect under the circumstances is achieved. In some embodiments, the method comprises administering from about 0.1 μg to about 50 mg of at least one compound described herein per kg of body weight of the subject. For a 70 kg patient, a dose of about 10 μg to about 200 mg of a compound disclosed herein will more commonly be used, depending on the physiological response of the subject.

[00118] By way of example only, a dosage of a compound described herein for a method of treating a disease described herein may be from about 0.001 to about 1 mg per kg of body weight of a subject per day; For example, approximately 0.001 mg, approximately 0.002 mg, approximately 0.005 mg, approximately 0.010 mg, 0.015 mg, approximately 0.020 mg, approximately 0.025 mg, approximately 0.050 mg, approximately 0 per kg of body weight per day. .075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg. In some embodiments, the dosage of a compound described herein for the described methods is from about 1 to about 1000 mg per kg of body weight of the subject being treated per day, e.g., about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg.

Method of treatment
[00119] The compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are useful for inhibiting the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the compounds and methods is TYK2.

[00120] The present invention provides compounds that are inhibitors of TYK2 and thus useful for treating one or more disorders associated with the activity of TYK2 or mutants thereof.

[00121] The present invention provides a method of treating a disease or disorder, wherein the disease or disorder is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disorder, or a transplant-related disease. , the method comprises administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Including.

[00122] In some embodiments, the disease or disorder is an autoimmune disease. In some embodiments, the disease or disorder is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[00123] In some embodiments, the disease or disorder is an inflammatory disease. In some embodiments, the inflammatory disease is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, inflammatory bowel disease.

[00124] In some embodiments, the disease or disorder is a proliferative disease. In some embodiments, the proliferative disease is cancer. In some embodiments, the disease or disorder is a proliferative disease. In some embodiments, the proliferative disease is a blood cancer. In some embodiments the proliferative disease is leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disease is polycythemia vera, myelofibrosis, essential or thrombocytosis.

[00125] In some embodiments, the disease or disorder is an endocrine disease. In some embodiments, the endocrine disease is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes.

[00126] In some embodiments, the disease or disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease.

[00127] In some embodiments, the proliferative disease is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation to the FERM domain, JH2 domain, or kinase domain. In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[00128] In some embodiments, the disease or disorder is related to transplantation. In some embodiments, the transplant-related disease or disorder is graft rejection or graft-versus-host disease.

[00129] In some embodiments, the disease or disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments the disease or disorder is associated with type I interferon signaling. In some embodiments the disease or disorder is associated with IL-10 signaling. In some embodiments the disorder is associated with IL-12 signaling. In some embodiments the disease or disorder is associated with IL-23 signaling.

[00130] The present invention provides treatment for inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, vascular hypersensitivity. inflammation, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquired, acne vulgaris, and other inflammatory skin conditions or a method of treating an allergic condition is provided.

[00131] The present invention provides methods of treating other diseases or conditions such as diseases or conditions that have an inflammatory component, such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis. Diseases and conditions that affect the nose, such as allergic rhinitis, and inflammatory diseases that involve an autoimmune reaction or have an autoimmune component or etiology, such as autoimmune blood diseases (e.g. hemolytic anemia, aplastic anemia, red cell anemia vera and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, renal disease, glomerular disease, alcoholic liver disease Diseases, multiple sclerosis, endocrine eye disorders, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cholangitis, uveitis (anterior and posterior), Sjögren's syndrome , keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic fever syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospiral renal disease, glaucoma, retinal disease, aging, headache , pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorder, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal hypoplasia disease, Behcet's disease, achromatopsia, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis, and exercise-induced), acute lung injury, acute Respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, ocular allergy, silica-induced disease, COPD (injury, airway inflammation, bronchial hyperresponsiveness, remodeling or reduction of disease progression), lung disease, cysts fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, myositis associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, or 2 type diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, total enteritis, epicondylitis, epididymitis, fasciitis, connective tissue inflammation, gastritis, Gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis , orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, Treatment of salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[00132] In some embodiments, the inflammatory disease is acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-related periodic syndrome (CAPS), or osteoarthritis.

[00133] In some embodiments, the inflammatory disease is a Th1 or Th17 mediated disease. In some embodiments, the Th17-mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[00134] In some embodiments, the inflammatory disease is Sjögren's syndrome, an allergic disease, osteoarthritis, an eye condition such as an ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal keratoconjunctivitis, or a disease that affects the nose, such as an allergy. It is sexual rhinitis.

combination therapy
[00135] In some cases, a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with a second therapeutic agent.

[00136] In some embodiments, the benefit experienced by a patient is due to the combination of one of the compounds described herein with a second therapeutic agent (including a therapeutic regimen) that also has a therapeutic benefit. Increased by administration.

[00137] In one particular embodiment, a compound described herein (or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof) is co-administered with a second therapeutic agent; a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated; This provides greater overall benefit than administration of either therapeutic agent alone.

[00138] In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient is simply additive of the two therapeutic agents, or the patient experiences a synergistic benefit. do.

[00139] In certain embodiments, when a compound disclosed herein is administered in combination with a second therapeutic agent, different therapeutically effective doses are used in the formulation of the pharmaceutical composition and/or treatment regimen. The compounds disclosed herein are utilized. Therapeutically effective doses of the drug and other drugs used in the combination treatment regimen may optionally be determined by means similar to those described herein above for the active agents themselves. The prophylactic/therapeutic methods described herein also include the use of metronomic dosing, ie, providing more frequent, lower doses to minimize toxic side effects. In some embodiments, a combination treatment regimen comprises the administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, as described herein. Includes treatment regimens that begin before, during, or after treatment with a second agent and continue until any time during treatment with the second agent or after the end of treatment with the second agent. Also, when a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a second agent used in combination are used simultaneously or at different times during the treatment period, and Also included are treatments administered at decreasing or increasing intervals. Combination therapy further includes periodic treatments that start and stop at different times to aid in the clinical management of the patient.

[00140] Medication regimens to treat, prevent, or ameliorate the condition sought to be alleviated will depend on various factors (e.g., the disease, disorder, or condition that the subject is suffering from; the subject's age, weight, sex, diet, and health status). It is understood that this is subject to change. Therefore, in some cases, the actual dosing regimen used will vary and, in some embodiments, deviate from the dosing regimen described herein.

[00141] For the combination therapies described herein, the doses of the co-administered compounds will vary depending on the type of co-medication used, the particular drug used, the disease or condition being treated, etc. . In additional embodiments, when co-administered with a second therapeutic agent, a compound provided by the invention is administered simultaneously or sequentially with the second therapeutic agent.

[00142] In combination therapy, multiple therapeutic agents, one of which is a compound described herein, are administered in any order or even simultaneously. If administration is simultaneous, multiple therapeutic agents may be administered in a single, combined form, or in multiple forms (e.g., as a single pill or as two separate pills), by way of example only. provided.

[00143] A compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a combination therapeutic agent are administered before, during, or after the onset of a disease or condition; The timing of administering compositions containing compounds will vary. Thus, in one embodiment, the compounds described herein are used as prophylactic agents and are administered continuously to a subject prone to developing a condition or disease in order to prevent the occurrence of the disease or condition. . In another embodiment, compounds and compositions are administered to a subject during or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as practicable after the onset of the disease or condition is detected or suspected and for the time necessary to treat the disease. In some embodiments, the length of treatment required varies, and the length of treatment is adjusted to suit the specific needs of each subject. For example, in certain embodiments, a compound described herein or a formulation containing the compound is administered for at least two weeks, about one month to about five years.

[00144] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with an adjuvant. In one embodiment, the therapeutic effectiveness of one of the compounds described herein is due to the adjuvant (i.e., the adjuvant has minimal therapeutic utility by itself, but when combined with another therapeutic agent) The overall therapeutic benefit to the patient is enhanced by the administration of

Intermediate 1

Step 1: Intermediate 1b
[00145] To a solution of Intermediate 1a (84 g, 363.6 mmol) in EtOH (464 mL) and concentrated HCl (116 mL) was added _SnCl2 (408 g, 2.16 mol). The reaction mixture was stirred at 60 °C for 3 h under _N2 . After cooling to room temperature, the mixture was poured into 2M aqueous NaOH (750 mL) pH=12 at 0°C. DCM (800 mL) was added to the mixture and the white solid was removed by filtration. The organic layer was separated and the aqueous phase was extracted with DCM (500 mL*2). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel flash column chromatography (petroleum ether/EtOAc=2/1) to give product intermediate 1b (49 g, 67% yield) as a yellow solid. LCMS[M+1] ⁺ =201.2.

Step 2: Intermediate 1c
[00146] A solution of intermediate 1b (49 g, 243.8 mmol) in AcOH (530 mL) and H ₂ O (100 mL) was cooled to 0° C. followed by NaNO ₂ (13.36 g, 193.8 mmol) in water (167 mL). 6 mmol) was added. The reaction mixture was stirred for 30 min at room temperature. After completion, gradual formation of a yellow precipitate was observed. The solid was collected by filtration, washed with 65% AcOH in water, and concentrated to give the product Intermediate 1c (40.7 g, 78% yield) as a yellow solid. LCMS[M+1] ⁺ =212.2.

Step 3: Intermediate 1d, intermediate 1d', and intermediate 1d''
[00147] To a solution of Intermediate 1c (2.0 g, 9.48 mmol) in THF (13 mL) was added NaH (545 mg, 14.2 mmol) and _CD3I (2.75 g, 18.96 mmol). The reaction mixture was stirred at 0° C. until room temperature for 16 h. After cooling to room temperature, the solids were filtered and the filtrate was concentrated. The crude product was purified by silica gel flash column chromatography (petroleum ether/DCM=1/1) to obtain product intermediate 1d (800 mg, 24% yield, retention time: 1.48 min) as a white solid. Intermediate 1d' (400 mg, 18% yield, retention time: 1.42 min) as a white solid and Intermediate 1d'' (500 mg, 25% yield, retention time: 1.33 min) as a white solid. Obtained. LCMS [M+1] ⁺ =229.2.

Step 4: Intermediate 1
[00148] To a solution of Intermediate 1d (800 mg, 3.5 mmol) in _CCl4 (10 mL) was added NBS (935 mg, 5.25 mmol) and AIBN (287 mg, 1.75 mmol). The reaction mixture was stirred at 80°C overnight. After cooling to room temperature, the solvent was removed and the residue was purified by silica gel flash column chromatography (petroleum ether/DCM=1/1) to yield the product intermediate 1 (700 mg, 65% yield) as a white solid. obtained as. LCMS[M+1] ⁺ =306.2.

Example 1: General procedure for the synthesis of Example 1

Step 1: Example 1b
[00149] To a solution of Example 1a (5.0 g, 36.34 mmol) and Et ₃ N (5.52 g, 54.50 mmol) in DCM (100 mL) was added 0 Boc ₂ O (9.52 g, 43.60 mmol). Added at °C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated and the crude product was purified by column chromatography eluting with DCM:MeOH (3%-5%) to give Example 1b (5.0 g, 68% yield) as a white solid. . LCMS[M-Boc+1] ⁺ =102.1.

Step 2: Example 1d
[00150] Intermediate 1 (459 mg, 1.49 mmol), TBAI (55 mg, 0.149 mmol) and NaH (72 mg, 1.79 mmol) were added to a solution of Example 1b (300 mg, 1.49 mmol) in THF (3 mL). Added at 0°C. The resulting mixture was stirred at room temperature for 3 h. H ₂ O (100 mL) was added and the mixture was extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine (30 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with petroleum ether/EtOAc (60/40) to give Example 1d (0.3 g, 92% yield) as a yellow oil. LCMS[M-2Boc+1] ⁺ =328.1.

Step 3: Example 1e
[00151] A solution of Example 1d (0.3 g, 0.72 mmol) in dioxane (3 mL) contains _Pd2 (dba) ₃ (66 mg, 0.0723 mmol), xanthophos (84 mg, 0.14 mmol), _{Cs2CO3 .} (707 mg, 2.17 mmol), and _NH2Boc (127 mg, 1.09 mmol) were added. The reaction mixture was degassed three times with argon and stirred at 100° C. for 3 h. The reaction mixture was poured into water (100 mL). The mixture was extracted with DCM (50 mL*3). The combined organic layers were washed with brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with MeOH/DCM (5%-10%) to give Example 1e (0.3 g, 47% yield) as a colorless oil. LCMS[M-Boc+1] ⁺ =265.2.

Step 4: Example 1f
[00152] To a solution of Example 1e (0.3 g, 0.645 mmol) in DCM (5 mL) was added TFA (2.58 g, 22.60 mmol) at room temperature. The resulting solution was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The pH of the residue was adjusted to 9 with 1M _NaHCO3 . The mixture was then extracted with DCM (50 mL*3). The combined organic layers were washed with brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The solvent was removed in vacuo. The residual Example 1f (0.17 g, 100% yield) was obtained as a yellow oil, which was used in the next step without further purification. LCMS[M-Boc+1] ⁺ =265.2.

Step 5: Example 1h
[00153] A solution of Example 1f (0.16 g, 0.61 mmol) in DCM (6 mL) contains DIEA (469 mg, 3.63 mmol), Example 1 g (198 mg, 0.61 mmol) and HATU (230 mg, 0.61 mmol). ) was added. The reaction mixture was stirred at room temperature for 1 h. Water (30 mL) was added and the mixture was extracted with DCM (10 mL*3). The combined organic layers were washed with brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography eluting with MeOH/DCM (7%) to give Example 1h (0.11 g, 11% yield) as a colorless solid. LCMS[M+1] ⁺ =573.2.

Step 6: Example 1i
[00154] To a solution of Example 1h (0.1 g, 0.17 mmol) in dioxane (1 mL) was added t-BuXphosPd G3 (28 mg, 0.035 mmol) and Cs ₂ CO ₃ (171 mg, 0.52 mmol). The reaction mixture was degassed three times with argon and stirred at 100° C. for 75 min. Water (50 mL) was added and the mixture was extracted with DCM (30 mL*3). The combined organic layers were washed with brine (30 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography eluting with MeOH/DCM (6%) to give Example 1i (0.1 g, yield: quantitative) as a yellow solid. LCMS[M+1] ⁺ =537.3.

Step 7: Example 1
[00155] To a solution of Example 1i (0.1 g, 0.19 mmol) in DCM (1 mL) was added TFA (531 mg, 4.66 mmol) at room temperature. The resulting solution was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The pH of the residue was adjusted to 9 with 1M _NaHCO3 . The mixture was then extracted with DCM (50 mL*3). The combined organic layers were washed with brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Pre-TLC (MeOH/DCM=10%) to give Example 1 (3.1 mg, 3.8% yield) as a white solid. LCMS[M+1] ⁺ =437.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.94 (s, 1H), 9.20 (d, J = 4.6 Hz, 1H), 8.14 (s, 1H), 7.84 (d, J = 1.8 Hz, 1H) , 7.57 (d, J = 5.2 Hz, 1H), 7.30 (s, 1H), 6.40 (s, 1H), 4.94 (d, J = 14.6 Hz, 1H), 4.60 (d, J = 14.5 Hz, 1H) , 3.83 (s, 1H), 3.73 (t, J = 8.4 Hz, 1H), 2.91 (d, J = 4.8 Hz, 3H), 2.27 (d, J = 10.3 Hz, 1H), 2.14 - 1.93 (m, 2H), 1.72 (d, J = 10.6 Hz, 1H), 1.61 - 1.42 (m, 2H).

Example A. TYK2 JH2 domain binding assay
[00156] The binding constants for the JH2 domain of the compounds described herein were determined by the following protocol for the KINOMEscan® assay (DiscoveRx). A partial-length construct of human TYK2 (JH2 domain pseudokinase) (amino acids G556-D888 based on reference sequence NP_003322.3) and a fusion protein of the DNA-binding domain of NFkB is expressed in transiently transfected HEK293 cells. . Extracts were extracted from these HEK293 cells in the presence of Protease Inhibitor Cocktail Complete (Roche) and Phosphatase Inhibitor Cocktail Set II (Merck) in M-PER extraction buffer (P ierce). TYK2 (JH2 domain pseudokinase) fusion protein is labeled with a chimeric double-stranded DNA tag containing an NFkB binding site fused to an amplicon for qPCR readout, which is added directly to the expression extract (during the binding reaction). The final concentration of DNA-tag is 0.1 nM).

[00157] Streptavidin-coated magnetic beads (Dynal M280) are treated with biotinylated small molecule ligand for 30 minutes at room temperature to generate an affinity resin for binding assays. Ligand-treated beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and remove non-specific Reduces binding.

[00158] Binding reactions were performed using 16 μl of DNA-tagged kinase extract, 3.8 μl of ligand-treated affinity beads, and 0.18 μl of test compound (PBS/0.05% Tween 20/10 mM DTT/0. Constructed by combining 1% BSA/2 μg/ml sonicated salmon sperm DNA). Extracts are used in direct binding assays at ≧10,000-fold total stock dilution (final DNA-tagged enzyme concentration <0.1 nM) without enzyme purification steps. The extract is DNA-tagged and diluted into the binding reaction in a two-step process. The first extract was prepared in 1× binding buffer (PBS/0.05% Tween20/10 mM DTT/0.1% BSA/2 μg/ml sonicated salmon sperm DNA) containing 10 nM DNA-tag. : Diluted to 100. This dilution is allowed to equilibrate for 15 minutes at room temperature and then diluted 1:100 with 1× binding buffer. Test compounds were prepared as 111x stocks in 100% DMSO. Kd was determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are dispensed in 100% DMSO by acoustic transfer (non-contact dispensing). Compounds are then diluted directly into the assay such that the final concentration of DMSO is 0.9%. All reactions are performed in polypropylene 384-well plates. Each had a final volume of 0.02 mL. The assay is incubated for 1 hour at room temperature with shaking. The beads are then pelleted and washed with wash buffer (1×PBS, 0.05% Tween20) to remove displaced kinase and test compound. The washed beads are resuspended in elution buffer (1×PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated for 30 minutes with shaking at room temperature. Kinase concentration in the eluate was measured by qPCR. The qPCR reaction is constructed by adding 2.5 μL of kinase eluate to 7.5 μL of qPCR master mix containing 0.15 μM amplicon primer and 0.15 μM amplicon probe. The qPCR protocol consisted of a 10 min hot start at 95°C followed by 35 cycles of 95°C for 15 seconds and 60°C for 1 minute.

[00159] Test compounds are prepared as 111x stocks in 100% DMSO. Kd was determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are dispensed in 100% DMSO by acoustic transfer (non-contact dispensing). Compounds are then diluted directly into the assay such that the final concentration of DMSO is 0.9%. Kd is determined using the highest concentration of compound at 30,000 nM. Kd measurements are performed twice.

[00160] Binding constants (Kd) were calculated using the Hill equation with standard dose-response curves:

[00161]Hill Slope was set to -1. The curves were fitted using nonlinear least squares fitting with the Levenberg-Marquardt algorithm (Levenberg, K., A method for the solution of certain non-linear problems in the least Quares, Q. Appl. Math. 2, 164-168 ( 1944)).
The results are shown in Table 1.

Example B: INFα-induced pSTAT5 in human PBMCs
[00162] Fresh human PBMC were resuspended in RPMI 1640 medium containing 10% FBS. Cells were plated in round-bottom 96-well plates at a concentration of 200,000 cells/well. A 10-point dilution series of test compounds (top dose 10 uM, 1:5 dilution) was added to the wells using a liquid dispenser (Tecan D300e) and incubated for 1 hour at 37C. Human INFα recombinant protein (R&D Systems) was then added to the wells at a final concentration of 5000 units/ml and incubated for 15 minutes at 37C. Cell lysates were prepared and analyzed by Phospho STAT5 (Tyr693) Kit (Meso Scale Discovery) according to the manufacturer's protocol.

[00163] For calculation of percent inhibition, relative pSTAT5 signal of each well = pSTAT5 signal of each well - mean pSTAT5 signal of baseline.

[00164] Percent inhibition = (average pSTAT5 signal of INFα-treated wells−relative pSTAT5 signal in each compound-containing well)/average pSTAT5 signal of INFα-treated wells*100%.

[00165] Curves were plotted as % inhibition (y-axis) versus compound concentration (x-axis) and fitted by GraphPad Prism 7.0 as log(inhibitor) versus normalized response--variable slope.
The control is BMS-986165:

[00166] The results are shown in Table 2.

Example C: Pharmaceutical composition Example C1: Parenteral composition
[00167] To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound described herein is dissolved in DMSO and then 10 mL of 0.9% sterile saline. mixed with. The mixture is incorporated into dosage unit form suitable for administration by injection.

Example C2: Oral composition
[00168] To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound described herein is mixed with 750 mg of starch. The mixture is incorporated into oral dosage units such as hard gelatin capsules suitable for oral administration.

Example C3: Sublingual (hard lozenge) composition
[00169] To prepare a pharmaceutical composition for buccal delivery such as a hard lozenge, combine 100 mg of a compound described herein with 420 mg powdered sugar, 1.6 mL light corn syrup, 2.4 mL of distilled water, and 0.42 mL of mint extract. The mixture is gently blended and cast to form a lozenge suitable for buccal administration.

[00170] The examples and embodiments described herein are merely illustrative and, in some embodiments, various modifications or changes are within the scope of the disclosure and the appended claims. .

Claims (57)

A compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
During the ceremony:
L is C ₁ -C ₄ alkylene; where 1 or 2 carbon atoms may be optionally substituted by heteroatoms selected from oxygen, sulfur, nitrogen, or phosphate; L is optionally 1 May be substituted with the above R ^L ;
Each R ^L is independently deuterium, halogen, -CN, -OR ^b , -NO ₂ , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C( =O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ - C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R ^L on the same carbon together form oxo, cycloalkyl, or heterocycloalkyl;
Ring A is heteroaryl and Ring B is cycloalkyl or heterocycloalkyl;
or Ring A is aryl or heteroaryl and Ring B is heterocycloalkyl or 5- to 8-membered cycloalkyl;
Each R ^A is independently deuterium, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O)2R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(=O)OR ^b , -OC(=O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C(= O) R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl , aryl, and heteroaryl may be independently optionally substituted with one or more R ^A1 ;
Each R ^A1 is independently deuterium, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(=O)OR ^b , -OC(=O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C( =O)R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C _{1 -C6} aminoalkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R ^A1 on the same carbon together form oxo;
n is 0-4;
Each R ^B is independently deuterium, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(=O)OR ^b , -OC(=O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C( =O)R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo Alkyl, aryl, and heteroaryl may be independently optionally substituted with one or more R ^B1 ;
or two R ^B on the same carbon together form oxo;
Each R ^B1 is independently deuterium, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O)R ^a , -C(=O)OR ^b , -OC(=O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O)NR ^c R ^d , -NR ^b C( =O)R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C _{1 -C6} aminoalkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R ^B1 on the same carbon together form oxo;
m is 0-4;
is a single or double bond;
X ¹ is N and X ² is -C=, or X ² is N and X ¹ is -C=;
Y ³ is CR ³ or N;
Y ⁶ is CR ⁶ or N;
Y ⁸ is CR ⁸ or N;
Y ⁹ is CR ⁹ or N;
R ³ , R ⁶ , R ⁸ , and R ⁹ are independently hydrogen, deuterium, halogen, -CN, -OR ^b , -SR ^b , -S(=O)R ^a , -S(=O) ₂ R ^a , -NO ₂ , -NR ^c R ^d , -NHS(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -OC(=O) R ^a , -C(=O)OR ^b , -OC(=O)OR ^b , -C(=O)NR ^c R ^d , -OC(=O)NR ^c R ^d , -NR ^b C(=O )NR ^c R ^d , -NR ^b C(=O)R ^a , -NR ^b C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl , C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl;
R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C 1 -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C _{1 -C 6} hydroxyalkyl, C ₁ -C ₆ amino alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be optionally substituted with one or more R ^4a ;
Each R ^4a is independently deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R ^4a on the same carbon together form oxo;
R ⁵ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl;
W is -O-, -S-, or -NR ⁷ -;
R ⁷ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl;
Each R ^a is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally one or more of oxo, deuterium, halogen, -CN, -OH, -OMe, -NH ₂ , -C(=O)Me, -C(=O)OH, -C(=O)OMe , C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;
Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally one or more of oxo, deuterium, halogen, -CN, -OH, -OMe, -NH ₂ , -C(=O)Me, -C(=O)OH, -C(=O ) OMe, optionally substituted with C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;
Each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ amino alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently optionally includes one or more of oxo, deuterium, halogen, -CN, -OH, -OMe, -NH ₂ , -C(=O)Me, -C(=O)OH, - optionally substituted with C(=O)OMe, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;
or R ^c and R ^d together with the nitrogen atom to which they are attached optionally contain one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH ₂ , -C( =O)Me, -C(=O)OH, -C(=O)OMe, _C1 - _C6 alkyl, or _C1 - _C6 haloalkyl to form a heterocycloalkyl optionally substituted. The compound of formula (I) is of formula (Ia):
2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. The compound of formula (I) is of formula (Ib):
2. A compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. The compound of formula (I) is of formula (Ic):
2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. The compound of formula (I) is of formula (Id):
2. A compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. The compound of formula (I) is of formula (Ie):
2. A compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. The compound of formula (I) is of formula (If):
2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. The compound of formula (I) is of formula (Ig):
2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. The compound of formula (I) is of formula (Ih):
2. A compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. The compound of formula (I) is of formula (Ii):
2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. The compound of formula (I) has formula (Ij):
2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, or Solvate. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, wherein ring A is aryl or heteroaryl and ring B is heterocycloalkyl. Japanese item. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, stereoisomerism, wherein ring A is aryl or heteroaryl and ring B is 5- to 8-membered cycloalkyl. body or solvate. 15. The compound according to claim 12 or 14, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Ring B is a 5- to 6-membered cycloalkyl. 16. The compound according to claim 12, 14, or 15, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Ring B is a 5-membered cycloalkyl. 14. The compound according to claim 12 or 13, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Ring B is a 5- to 6-membered heterocycloalkyl. 18. The compound according to claim 12, 13, or 17, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Ring B is a 5-membered heterocycloalkyl. 19. The compound according to any one of claims 12 to 18, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Ring A is a bicyclic heteroaryl. A compound according to any one of claims 12 to 19, or a pharmaceutically acceptable compound thereof, wherein Ring A is indolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiophenyl, benzothiazolyl, benzofuranyl, or benzoxazolyl. salts, stereoisomers, or solvates. 19. The compound according to any one of claims 12 to 18, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Ring A is a monocyclic heteroaryl. 22. A compound according to any one of claims 12 to 18 and 21, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Ring A is pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl. 15. The compound according to claim 13 or 14, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Ring A is phenyl. 24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Y ⁹ is N. 25. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Y ⁶ is CR ⁶ . 26. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein R ⁶ is hydrogen. 27. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Y ³ is CR ³ . 28. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein R ³ is hydrogen. 29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Y ⁸ is N. 30. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Y ⁸ is CR ⁸ . 31. A compound according to any of claims 1 to 28 and 30, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein R ⁸ is hydrogen. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable compound thereof, wherein R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. salts, stereoisomers, or solvates. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt, stereoisomer, or solvent thereof, wherein R ⁴ is C ₁ -C ₆ alkyl or C ₁ -C ₆ deuteroalkyl. Japanese item. 34. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein R ⁵ is hydrogen. 35. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein W is -O-. 35. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein W is -NR ⁷ -. 37. A compound according to any of claims 1-34 and 36, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein R ⁷ is hydrogen or C ₁ -C ₆ alkyl. Each R ^A is independently deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R ^A1 . or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. Each R ^A is independently deuterium, halogen, C ₁ -C ₆ alkyl, C 1 -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C _{1 -C 6} hydroxyalkyl, C ₁ -C ₆ aminoalkyl , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R ^A1 39. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. each R ^A is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, aryl, or heteroaryl; , and the heteroaryl may be independently optionally substituted with one or more R ^A1 , or a pharmaceutically acceptable salt thereof, stereoisomer body or solvate. 39. According to any one of claims 1 to 38, each R ^A is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl. or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. A compound according to any one of claims 1 to 38, or the like, wherein each R ^A is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl, or Pharmaceutically acceptable salts, stereoisomers, or solvates. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein each R ^A is independently C ₁ -C ₆ deuteroalkyl. thing. 44. A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein n is 1 or 2. 44. A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein n is 1. L is C ₂ -C ₄ alkylene; where one carbon atom may be optionally replaced by a heteroatom selected from oxygen, sulfur, or nitrogen; L is optionally one or more R ^L 46. A compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, optionally substituted with . L is C ₂ -C ₃ alkylene; where one carbon atom may be optionally replaced by a heteroatom selected from oxygen, sulfur, or nitrogen; L is optionally one or more R ^L 46. A compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, optionally substituted with . L is C ₂ -alkylene; in which one carbon atom may be optionally substituted by a heteroatom selected from oxygen, sulfur or nitrogen; L is optionally substituted with one or more R ^L 46. A compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. 49. A compound according to any one of claims 46 to 48, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the heteroatom is oxygen or sulfur. 50. A compound according to any one of claims 46 to 49, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the heteroatom is oxygen. A compound according to any one of claims 1 to 50, wherein L is -CH ₂ -O- or -O-CH ₂ -, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof. thing. The compound
A compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, selected from: A therapeutically effective amount of a compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable excipient. A pharmaceutical composition comprising an agent. 53. A method of inhibiting the TYK2 enzyme in a patient or biological sample, comprising treating said patient or biological sample with a compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof. A method comprising the step of contacting a stereoisomer or solvate. 53. A method of treating a TYK2-mediated disease, comprising administering to a patient in need of treatment a compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt, stereoisomer thereof. A method comprising the step of administering a solvate or a solvate. 56. The method of claim 55, wherein the TYK2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disorder, or a transplant-related disease. 56. The method of claim 55, wherein the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.